The lethal effects of acid rain on aquatic biosystems appear to be due to not only acidity but also to the metals, especially aluminum, that are mobilized from soil and rock. In fish there is evidence that, in addition to the water aluminum concentration and pH value, the concomitant calcium concentration plays a significant role in the survival rate; this situation appears to also apply to the toxicity of aluminum in man. In patients with chronic renal failure aluminum is recognized as a toxic agent; the prevalence of toxic phenomenon in these patients has a geographical variation associated with a high aluminum and low calcium concentratin in their domestic water supplies. In patients with normal renal function, aluminum has been identified as a factor in the etiology of specific neurologicla disorders, with a high prevalence, in two areas of the World. Soid and drinking water from these areas had a high aluminum content with low concentrations of calcium and magnesium. There is some evidence that secondary hyperparathyroidism, provoked by the chronic environmental deficiency of calcium and magnesium, may result in an increased intestinal absorption of aluminum and its subsequent deposition in the central nervous system. Aluminum has bene included among the possible pathogenic factors in Alzheimer's disease. The latter may be the major health hazard to man from acid rain due to its action of increasing the water content of aluninum. The critical and unique area that this proposal investigates, in an experimental animal model, rabbits, is the effect of the long-term oral intake of aluminum in drinking water, with concomitant variable concentrations of calcium and magnesium. The subsequent accumulation of aluminum will be monitored chemically in the central nervous system and other organs as will the development of any histological changes as evaluated by light and electron microscopy, immunohistochemistry (using monoclonal antibodies to phosphorylated neurofilament epitopes which may detect early neurofibrillary tangles) and electron beam x-ray micoranalysis. Tissue culture of areas of brain showing pathology invivo will be evaluated in vitro using similar morphologic and histochemical techniques inorder to correlate more precisely aluminum levels with cell changes. Aluminum loading will also be studied for comparative purposes by the intravenous route using a recently developed compound (aluminum maltol) (67) which is water soluble and has a neutral pH.